The invention provides a method for inhibiting the binding of a biguanide antimicrobial in aqueous solution to a hydrogel in contact with said solution comprising providing in said solution an amount of cyclodextrin sufficient to inhibit sorption of the biguanide antimicrobial to a hydrogel.

This invention relates generally to a composition and method for storing, preserving and dispensing solutions for cleaning and disinfecting contact lenses.
Biguanide antimicrobials such as alexidine and PHMB are widely used as antimicrobials in ophthalmic solutions, for example, contact lens cleaning, disinfecting and have been commercialized in various products, typically at levels of about 1 ppm or less for use with soft contact lenses. It is generally desirable to provide the lowest possible level of antimicrobial that is consistent with reliable disinfection in order to provide a generous margin for safety and comfort.
U.S. Pat. No. 4,758,595 to Ogunbiyi et al. discloses a contact-lens solution containing a polyaminopropyl biguanide (PAPB), also known as polyhexamethylene biguanide (PHMB) in combination with a borate buffer. These disinfecting and preservative solutions are especially noteworthy for their broad spectrum of bactericidal and fungicidal activity at low concentrations coupled with very low toxicity when used with soft-type contact lenses.
Some of the most popular products for disinfecting lenses are multipurpose solutions that can be used to clean, disinfect and wet contact lenses, followed by direct insertion (placement on the eye) without rinsing. Obviously, the ability to use a single solution for contact-lens care is an advantage. Such a solution, however, must be particularly gentle to the eye, since, as indicated above, some of the solution will be on the lens when inserted and will come into contact with the eye.
With conventional contact-lens cleaners or disinfectants, including multi-purpose solutions, lens wearers typically need to digitally or manually rub the contact lenses (typically between a finger and palm or between fingers) during treatment of the contact lenses. The necessity for the daily xe2x80x9crubbingxe2x80x9d of contact lenses adds to the time and effort involved in the daily care of contact lenses. Many contact-lens wearers dislike having to perform such a regimen or consider it to be an inconvenience. Some wearers may be negligent in the proper xe2x80x9crubbingxe2x80x9d regimen, which may result in contact-lens discomfort and other problems. Sometimes rubbing, if performed too rigorously, which is particularly apt to occur with beginning lens wearers, may damage the lenses. This can be problematic when a replacement lens is not immediately available.
Contact lens solutions that qualify as a xe2x80x9cChemical Disinfecting Solutionxe2x80x9d do not require rubbing to meet biocidal performance criteria (for destroying representative bacteria and fungi) set by the US Food and Drug Administration (FDA) under the Premarket Notification (510 k) Guidance Document For Contact Lens Care Products, May 1, 1997. In contrast, a contact-lens solution, referred to as a xe2x80x9cChemical Disinfecting System,xe2x80x9d that does not qualify as a Chemical Disinfecting Solution, requires a rubbing regimen to pass biocidal performance criteria. Traditionally, multi-purpose solutions (used for disinfecting and wetting or for disinfecting, cleaning, and wetting) have qualified as a Chemical Disinfecting System, but not as a Chemical Disinfecting Solution.
A Chemical Disinfecting Solution would generally require a more efficacious or stronger disinfectant than a Chemical Disinfecting System. The stronger the biocidal effect of a solution, however, the more likely that it may exhibit toxic effects or adversely effect lens-wearer comfort. For example, many very efficacious bactericides used in other contexts, such as mouthwashes, cosmetics, or shampoos, while being sufficiently safe for use in such products, would be too toxic for ophthalmic use, especially for use with soft lenses because of the above-mentioned tendency of soft lenses to bind chemicals and the sensitivity of eye tissues. Similarly, the concentrations of certain bactericides may need to be within lower limits in solutions for use with soft contact lenses than in other products or in solutions for other types of lenses, especially when such solutions are not rinsed from the contact lens before placing the lens in the eye.
It would be desirable to obtain a contact-lens solution that would simultaneously provide both (1) an increased level and/or broader spectrum of biocidal activity, and (2) a low order of toxicity to eye tissue, such that the solution can be used to treat a contact lens such that the lens can subsequently be placed on the eye without rinsing the solution from the lens. While challenging to develop, it would be especially desirable to obtain a Chemical Disinfecting Solution that could be used for soft contact lenses and that would allow direct placement of a contact lens on an eye following soaking in the solution and/or rinsing and rewetting with the solution. Such a product may provide increased efficacy, resulting in greater protection to the lens wearer against infection caused by microorganisms, while providing maximum convenience. Finally, it would be desirable for the biocidal efficacy of the disinfecting solution to be sufficiently high to achieve the efficacious disinfection, or at least not inherently inefficacious disinfection, of a contact lens with respect to bacteria and fungi in the event, for whatever reason, that the contact lens wearer does not carry out a regimen involving mechanical rubbing or the like using the contact-lens solution.
The invention provides, in a first aspect, a method and composition for inhibiting the binding of a biguanide antimicrobial in aqueous solution to a hydrogel in contact with said solution comprising providing in said solution an amount of cyclodextrin sufficient to inhibit binding of the biguanide antimicrobial to the hydrogel. The composition of the invention may comprise additional components, for example, at least one selected from the group consisting of buffers, sequestering and/or chelating agents, tonicity adjusting agents, surfactants, pH adjusting agents and viscosity builders.
The invention also provides a method and composition for cleaning contact lenses is provided comprising contacting the lenses with a composition containing an effective amount of one or more biguanide antimicrobials and from 0.0001% to about 10% by weight of one or more cyclodextrins for a time sufficient to clean the lenses. In a preferred embodiment, the composition is a multipurpose contact lens solution for cleaning and disinfecting contact lenses, and contains other components such as including buffers, chelating and/or sequestering agents, tonicity adjusting agents, surfactants, pH adjusting agents and viscosity builders.
The invention still further provides a composition for rewetting, disinfecting and/or cleaning hydrogel contact lenses comprising at least one biguanide antimicrobial and an amount of cyclodextrin that is:
(a) insufficient of itself to effectively clean contact lenses if that amount of cyclodextrin were present in the solution in the absence of at least one other cleaning agent; and
(b) at least sufficient to inhibit the sorption of a biguanide antimicrobial to the hydrogel contact lenses.
In a preferred embodiment, the composition comprises a biguanide antimicrobial selected from the group consisting of poly(hexamethylene)biganide and alexidine. The composition preferably comprises at least one buffer at least one chelating agent or sequestering agent. The composition may suitably comprise at least one tonicity-adjusting agent, as well as surfactants, pH adjusting agents and viscosity builders.
The composition of the present invention is, in one embodiment, an aqueous biguanide-containing solution disinfecting solution, for example, a multipurpose contact lens solution. The composition of the invention contains one or more cyclodextrins together with one or more biguanide antimicrobials in a suitable carrier. Other active or inactive components can also be employed in the compositions, including buffers, chelating and/or sequestering agents, tonicity adjusting agents, surfactants, pH adjusting agents and viscosity builders.
The cyclodextrins useful in the present invention are cyclic oligosaccharides that may be produced by the enzymatic degradation of starch and have multiple glucose or glucopyranose units, usually 6 to 8 units. Depending on the particular preparation reaction conditions employed, cyclodextrins generally contain six, seven or eight of such units, connected by alpha-(1,4)bonds. The six, seven or eight unit cyclodextrins are commonly known as alpha-, beta-, and gamma-cyclodextrins, respectively.
Cyclodextrins have the shape of truncated cones with primary and secondary hydroxyl groups located at opposite ends of the torus. The glucosyl-o-bridges point into the center of the molecule and the primary hydrogel groups project from one outer edge while the secondary hydroxyl groups project from the other edge. The result is a molecule with a relatively hydrophobic center and a hydrophilic outer surface. These shapes and hydrophilic/hydrophobic domains provide for inclusion or incorporation of guest molecules into the center of the molecule.
Cyclodextrins are well known and are commercially produced by the enzymatic degradation of starch. For example, beta-cyclodextrin is the major product of the reaction between the enzyme cyclodextrin transglycosylase and a starch solution pretreated with gamma-amylase.
As used herein, the term xe2x80x9ccyclodextrinsxe2x80x9d includes all cyclodextrin derivatives, such as cyclodextrin carbonates, ethers, esters, and polyethers; polymers or copolymers of polymerized cyclodextrins, such as polymerized beta-cyclodextrins; and substituted cyclodextrins such as those with functional groups bonded to one or more of the hydroxyl groups. Suitable function groups include, but are not limited to, methyl, ethyl, hydroxyethyl, and hydroxypropyl and acetyl groups. The cyclodextrin derivatives can also include cyclodextrins with functional groups replacing one or more of the hydroxyl groups such as amino-cyclodextrin, iodo-cyclodextrin and cyclodextrin sulfate. Some of these functional groups may also contribute preserving or disinfecting properties.
The preferred cyclodextrins are the beta-cyclodextrins and most preferred are beta-cyclodextrin selected from beta-cyclodextrin, hydroxypropyl beta-cyclodextrin, methyl beta-cyclodextrin and hydroxyethyl beta-cyclodextrin when the cyclodextrin compositions are employed at elevated temperatures.
The present invention employs an effective amount of cyclodextrin to inhibit the sorption of the biguanide by hydrogels, especially hydrogels suitable for fabricating contact lenses. The term xe2x80x9ceffective amount of cyclodextrinxe2x80x9d as used herein means an amount of cyclodextrin sufficient to inhibit the sorption of the biguanide antimicrobial present in solution to the hydrogel. The amount of cyclodextrin may also vary with the required contact time between the hydrogel and the solution. For example, if the solution is a multipurpose solution for cleaning and disinfecting hydrogel contact lenses, the amount of cyclodextrin present in the multipurpose solution is preferably at least sufficient to inhibit the sorption of the biguanide antimicrobial.
In addition to multipurpose solutions, the invention is useful with ophthalmic solutions generally, including moisturizing eye drops and rewetting solutions, merely to name two examples.
The biguanide disinfectant is suitably present in concentration of from about 0.5 to about 10 ppm, preferably from about 1 to about 4 ppm. The cyclodextrin is suitably present in concentration of from about 0.1 to about 1.0 weight percent, preferably from about 0.2 to about 0.4 weight percent.
Hydrogels comprise hydrated, crosslinked polymeric systems containing water in an equilibrium state. Conventional hydrogel lens materials include polymers containing monomers such as 2-hydroxyethyl methacrylate (HEMA), glyceryl methacrylate, N-vinylpyrrolidone (NVP) and dimethacrylamide.
Flexible ophthalmic lens materials useful in the present invention include silicone hydrogels as well as conventional hydrogels and low-water elastomeric materials. Examples of flexible ophthalmic lens materials useful in the present invention are taught in U.S. Pat. No. 5,908,906 to Kxc3xcnzler et al.; U.S. Pat. No. 5,714,557 to Kxc3xcinzler et al.; U.S. Pat. No. 5,710,302 to Kxc3xcinzler et al.; U.S. Pat. No. 5,708,094 to Lai et al.; U.S. Pat. No. 5,616,757 to Bambury et al.; U.S. Pat. No. 5,610,252 to Bambury et al.; U.S. Pat. No. 5,512,205 to Lai; U.S. Pat. No. 5,449,729 to Lai; U.S. Pat. No. 5,387,662 to Kxc3xcnzler et al. and U.S. Pat. No. 5,310,779 to Lai; which patents are incorporated by reference as if set forth at length herein.
U.S. Pat. Nos. 6,037,328, 6,008,317, 5,981,675, 5,981,669, 5,969,076, 5,945,465, 5,914,355, 5,858,937, 5,824,719 and 5,726,733 teach ophthalmic lens materials containing HEMA monomers.
U.S. Pat. Nos 6,071,439, 5,824,719, 5,726,733, 5,708,094, 5,610,204, 5,298,533, 5,270,418, 5,236,969 and 5,006,622 teach ophthalmic lens materials containing glyceryl methacrylate monomers.
U.S. Pat. Nos. 6,008,317, 5,969,076, 5,908,906, 5,824,719, 5,726,733, 5,714,557, 5,710,302, 5,708,094, 5,648,515 and 5,639,908 teach ophthalmic lens materials containing NVP monomers.
U.S. Pat. Nos. 5,539,016, 5,512,205, 5,449,729, 5,387,662, 5,321,108 and 5,310,779 teach ophthalmic lens materials containing dimethacrylamide monomers.
The preferred conventional hydrogel materials typically contain HEMA, NVP and TBE (4-t-butyl-2-hydroxycyclohexyl methacrylate). Polymacon(trademark) materials, for example the Soflens 66(trademark) brand contact lenses (commercially available from Bausch and Lomb Incorporated of Rochester, N.Y.) are examples of particularly preferred conventional hydrogel materials.
Silicone hydrogels generally have a water content greater than about five weight percent and more commonly between about ten to about eighty weight percent. Materials are usually prepared by polymerizing a mixture containing at least one silicone-containing monomer and at least one hydrophilic monomer. Either the silicone-containing monomer or the hydrophilic monomer may function as a crosslinking agent (a crosslinker being defined as a monomer having multiple polymerizable functionalities) or a separate crosslinker may be employed. Applicable silicone-containing monomeric units for use in the formation of silicone hydrogels are well known in the art and numerous examples are provided in U.S. Pat. Nos. 4,136,250; 4,153,641; 4,740,533; 5,034,461; 5,070,215; 5,260,000; 5,310,779; and 5,358,995.
A preferred silicone hydrogel material comprises (in the bulk monomer mixture that is copolymerized) 5 to 50 percent, preferably 10 to 25, by weight of one or more silicone macromonomers, 5 to 75 percent, preferably 30 to 60 percent, by weight of one or more polysiloxanylalkyl (meth)acrylic monomers, and 10 to 50 percent, preferably 20 to 40 percent, by weight of a hydrophilic monomer. In general, the silicone macromonomer is a poly(organosiloxane)capped with an unsaturated group at two or more ends of the molecule. In addition to the end groups in the above structural formulas, U.S. Pat. No. 4,153,641 to Deichert et al. discloses additional unsaturated groups, including acryloxy or methacryloxy. Fumarate-containing materials such as those taught in U.S. Pat. No. 5,512,205; 5,449,729; and 5,310,779 to Lai are also useful substrates in accordance with the invention. Preferably, the silane macromonomer is a silicon-containing vinyl carbonate or vinyl carbamate or a polyurethane-polysiloxane having one or more hard-soft-hard blocks and end-capped with a hydrophilic monomer.
Suitable hydrophilic monomers include those monomers that, once polymerized, can form a complex with poly(acrylic acid). The suitable monomers form hydrogels useful in the present invention and include, for example, monomers that form complexes with poly(acrylic acid) and its derivatives. Examples of useful monomers include amides such as N,N-dimethyl acrylamide, N,N-dimethyl methacrylamide, cyclic lactams such as N-vinyl-2-pyrrolidone and poly(alkene glycol)s functionalized with polymerizable groups. Examples of useful functionalized poly(alkene glycol)s include poly(diethylene glycol)s of varying chain length containing monomethacrylate or dimethacrylate end caps. In a preferred embodiment, the poly(alkene glycol)polymer contains at least two alkene glycol monomeric units. Still further examples are the hydrophilic vinyl carbonate or vinyl carbamate monomers disclosed in U.S. Pat. No. 5,070,215, and the hydrophilic oxazolone monomers disclosed in U.S. Pat. No. 4,910,277. Other suitable hydrophilic monomers will be apparent to one skilled in the art. In a particularly preferred embodiment, the hydrophilic monomers used in the contact lens material are capable of forming a stable complex with a cationic polysaccharide.
Rigid ophthalmic lens materials include rigid-gas-permeable (xe2x80x9cRGPxe2x80x9d) materials. RGP materials typically comprise a hydrophobic crosslinked polymer system containing less than 5 wt. % water. RGP materials useful in accordance with the present invention include those materials taught in U.S. Pat. No. 4,826,936 to Ellis; U.S. Pat. No. 4,463,149 to Ellis; U.S. Pat. No. 4,604,479 to Ellis; U.S. Pat. No. 4,686,267 to Ellis et al.; U.S. Pat. No. 4,826,936 to Ellis; U.S. Pat. No. 4,996,275 to Ellis et al.; U.S. Pat. No. 5,032,658 to Baron et al.; U.S. Pat. No. 5,070,215 to Bambury et al.; U.S. Pat. No. 5,177,165 to Valint et al.; U.S. Pat. No. 5,177,168 to Baron et al.; U.S. Pat. No. 5,219,965 to Valint et al.; U.S. Pat. No. 5,336,797 to McGee and Valint; U.S. Pat. No. 5,358,995 to Lai et al.; U.S. Pat. No. 5,364,918 to Valint et al.; U.S. Pat. No. 5,610,252 to Bambury et al.; U.S. Pat. No. 5,708,094 to Lai et al; and U.S. Pat. No. 5,981,669 to Valint et al. U.S. Pat. No. 5,346,976 to Ellis et al. teaches a preferred method of making an RGP material. The patents mentioned above are incorporated by reference as if set forth at length herein.
The cyclodextrin concentrations useful herein may be adjusted by one of ordinary skill in the art depending upon the desired contact time between the biguanide-containing solution and the poly(ethylene).
The cyclodextrin composition may contain a preserving or disinfecting amount of one or more antimicrobial agents in addition to the biguanide antimicrobial. The subject solution preferably includes at least one antimicrobial agent. As used herein, antimicrobial agents are defined as non-oxidative organic chemicals that derive their antimicrobial activity through a chemical or physiochemical interaction with the microbial organisms. Preferred antimicrobials are the quaternary ammonium compounds and biguanides.
Representative examples of the quaternary ammonium compounds are compositions comprised of benzalkonium halides or, for example, balanced mixtures of n-alkyl dimethyl benzyl ammonium chlorides. Other examples include polymeric quaternary ammonium salts used in ophthalmic applications such as poly[(dimethyliminio)-2-butene-1,4-diylchloride], [4-tris(2-hydroxyethyl)ammonio]-2-butenyl-w-[tris(2-hydroxyethyl)ammonio]dichloride (chemical registry number 75345-27-6) generally available as Polyquaternium 1(copyright) from ONYX Corporation.
Representative biguanides are the bis(biguanides), such as alexidine or chlorhexidine or salts thereof, and polymeric biguanides such as polymeric hexamethylene biguanides (PHMB).
Polymeric hexamethylene biguanides (commercially available from Zeneca, Wilmington, Del.), their polymers and water-soluble salts being most preferred. Generally, the hexamethylene biguanide polymers, also referred to as polyaminopropyl biguanide (PAPB), have molecular weights of up to about 100,000. Such compounds are known and are disclosed in U.S. Pat. No. 4,758,595 which patent is incorporated herein be reference.
A disinfecting amount of antimicrobial agent is an amount that will at least partially reduce the microorganism population in the formulations employed. Preferably, a disinfecting amount is that which will reduce the microbial burden by two log orders in four hours and more preferably by one log order in one hour. Most preferably, a disinfecting amount is an amount which will eliminate the microbial burden on a contact lens when used in regimen for the recommended soaking time (FDA Chemical Disinfection Efficacy Testxe2x80x94July, 1985 Contact Lens Solution Draft Guidelines). Typically, such agents are present in concentrations ranging from about 0.00001 to about 0.5% (w/v), and more preferably, from about 0.00003 to about 0.5% (w/v).
A second disinfectant/germicide can be employed as a solution preservative, but it may also function to potentiate, compliment or broaden the spectrum of microbiocidal activity of another germicide. This includes microbiocidally effective amounts of germicides which are compatible with and do not precipitate in the solution, in concentrations ranging from about 0.00001 to about 0.5 weight percent, and more preferably, from about 0.0001 to about 0.1 weight percent. Suitable complementary germicidal agents include, but are not limited to thimerosal or other phenylmercuric salts, sorbic acid, alkyl triethanolamines, and mixtures thereof.
The acid-addition salts of the germicides used in the present composition may be derived from an inorganic or organic acid. In most circumstances it is preferable that the salts be derived from an acid which is readily water-soluble and which affords an anion which is suitable for human usage, for example a pharmaceutically acceptable anion. Examples of such acids are hydrochloric, hydrobromic, phosphoric, sulphuric, acetic, D-gluconic, 2-pyrrolidino-5-carboxylic, methanesulphonic, carbonic, lactic and glutamic acids. The hydrochloride salt is preferred.
In the present application, the amount of the germicide or other components in a solution according to the present invention refers to the amount formulated and introduced into the solution at the time the solution is made.
Suitable chemical antimicrobial agents, as the term is used herein, include quaternary ammonium salts and polymers used in ophthalmic applications such as poly[(dimethyliminio)-2-butene-1,4-diyl chloride], [4-tris(2-hydroxyethyl)ammonio]-2-butenyl-W-[tris(2-hydroxyethyl)ammonio]dichloride (chemical registry number 75345-27-6), commercially available from ONYX Corporation; halides; trialkylammonium halides; biguanides such as salts of alexidine, alexidine free base, salts of chlorhexidine, hexamethylene biguanides and their polymers; and the like. The salts of alexidine and chlorhexidine can be either organic or inorganic and are typically gluconates, nitrates, acetates, phosphates, sulfates, halides and the like.
Suitable oxidative antimicrobial agents, as the term is used herein, include any peroxide sources which produce active oxygen in solution and any iodine liberating sources which produce preserving or disinfecting amounts of iodine compounds in solution. Examples of such agents include hydrogen peroxide and its alkali metal salts; alkali metal perborates and persulfates; alkali metal carbonate peroxide; diperisophthalic acid; peroxydiphosphate salts; sodium aluminium aminohydroperoxide; iodine and iodophors. Preferred oxidative antimicrobial agents are peroxides and iodophors. The antimicrobial agents can also be employed after the cleaning step using the cyclodextrin composition. In this application, the cleaning step would be followed with a disinfecting step in a conventional regimen.
A preserving amount of an antimicrobial agent is an amount that will substantially inhibit the microorganism population from growing while a disinfecting amount is an amount that will reduce the microorganism population. Preferably, a preserving amount of antimicrobial agent will substantially inhibit the microorganism population growth for at least thirty (30) days after exposure to environmental air. Preferably, a disinfecting amount of an antimicrobial agent is that which will reduce the microbial burden by about two log orders in four hours and, more preferably, by about one log order in one hour. Typically, such agents are present in concentrations ranging from about 0.00001% to about 0.5% (w/v), and more preferably, from about 0.00003% to about 0.05% (w/v).
The pH of the present solutions should be maintained within the range of 5.0 to 8.0, more preferably about 6.0 to 8.0, most preferably about 6.5 to 7.8, suitable buffers may be added, such as boric acid, sodium borate, potassium citrate, citric acid, sodium bicarbonate, TRIS, and various mixed phosphate buffers (including combinations of Na2HPO4, NaH2PO4 and KH2PO4) and mixtures thereof. Borate buffers are preferred, particularly for enhancing the efficacy of biguanides.
Generally, buffers will be used in amounts ranging from about 0.05 to 2.5 percent by weight, and preferably, from 0.1 to 1.5 percent. The disinfecting/preserving solutions of this invention preferably contain a borate or mixed phosphate buffer, containing one or more of boric acid, sodium borate, potassium tetraborate, potassium metaborate or mixtures of the same. In one embodiment, the solution of the invention may include a buffering system having a buffering capacity up to 40 ml of 0.01N HCl to change pH from pH 7.4 to 6.4 and up to 25 ml of 0.01 N NaOH to change pH from pH 7.4 to 8.4 and comprising 0.05xcx9c2.5% by weight of phosphate salt and 0.1xcx9c5.0% by weight of boric acid. The composition optionally further comprises an alkali or alkaline earth metal carbonates including sodium bicarbonate, sodium carbonate, potassium carbonate, potassium bicarbonate, and sodium bicarbonate. The most preferred carbonate is sodium carbonate.
If a carbonate buffer is used, it is suitably present in the amount of a buffering system having a buffering capacity up to 40 ml of 0.01 NHCl to change pH from pH 7.4 to 6.4 and up to 25 ml of 0.01xcx9cNaOH to change pH from pH 7.4 to 8.4 and comprising 0.05xcx9c2.5% by weight of phosphate salt and 0.1xcx9c5.0% by weight of boric acid.
The composition of the present invention may optionally includes a phosphonic acid, or its physiologically compatible salt, that is represented by the following Formula (I):
wherein Z is a connecting radical equal in valence to n, wherein n is an integer from 1 to 6, preferably 1 to 3.
If the solution contains a phosphonic acid buffer, the phosphonic acid buffer is suitably present in a concentration of at least 0.003 percent weight by volume of the subject phosphonic compound in the total solution, preferably 0.005 to 2.5 percent weight by volume and more preferably about 0.01 to 0.5 percent weight by volume in the total solution.
In a preferred embodiment, the solution comprises both a phosphate buffer and a borate buffer.
In addition to buffering agents, in some instances it may be desirable to include chelating and/or sequestering agents in the present solutions in order to bind metal ions which might otherwise react with the lens and/or protein deposits and collect on the lens. Dequest 2016 and its salts (disodium) are preferred examples. They are usually added in amounts ranging from about 0.01 to about 0.3 weight percent. Other suitable sequestering agents include gluconic acid, citric acid, tartaric acid (EDTA) and their salts, e.g. sodium salts.
Typically, the aqueous solutions of the present invention for treating contact lenses are also adjusted with tonicity agents, to approximate the osmotic pressure of normal lacrimal fluids which is equivalent to a 0.9 percent solution of sodium chloride or 2.5 percent of glycerol solution. The solutions are made substantially isotonic with physiological saline used alone or in combination, otherwise if simply blended with sterile water and made hypotonic or made hypertonic the lenses will lose their desirable optical parameters. Correspondingly, excess saline may result in the formation of a hypertonic solution that will cause stinging and eye irritation.
Examples of suitable tonicity adjusting agents include, but are not limited to: sodium and potassium chloride, dextrose, glycerin, calcium and magnesium chloride. These agents are typically used individually in amounts ranging from about 0.01 to 2.5% (w/v) and preferably, form about 0.2 to about 1.5% (w/v). Preferably, the tonicity agent will be employed in an amount to provide a final osmotic value of 200 to 450 mOsm/kg and more preferably between about 250 to about 350 mOsm/kg, and most preferably between about 280 to about 320 mOsm/Kg.
The present solution comprises at least one surfactant. Suitable surfactants can be either amphoteric, cationic, anionic, or nonionic which may be present (individually or in combination) in amounts up to 15 percent, preferably up to 5 percent weight by volume (w/v) of the total composition (solution). Preferred surfactants are amphoteric or nonionic surfactants; which when used impart cleaning and conditioning properties. The surfactant should be soluble in the eye care solution and non-irritating to eye tissues. Many nonionic surfactants comprise one or more chains or polymeric components having oxyalkylene (xe2x80x94Oxe2x80x94Rxe2x80x94) repeats units wherein R has 2 to 6 carbon atoms. Preferred non-ionic surfactants comprise block polymers of two or more different kinds of oxyalkylene repeat units, which ratio of different repeat units determines the HLB of the surfactant. Satisfactory non-ionic surfactants include polyethylene glycol esters of fatty acids, e.g. coconut, polysorbate, polyoxyethylene or polyoxypropylene ethers of higher alkanes (C12-C18). Examples of the preferred class include polysorbate 20 (available under the trademark Tween(copyright) 20), polyoxyethylene (23) lauryl ether (Brij(copyright) 35), polyoxyethyene (40) stearate (Myrj(copyright) 52), polyoxyethylene (25) propylene glycol stearate (Atlas(copyright) G 2612). One non-ionic surfactant in particular consisting of a poly(oxypropylene)-poly(oxyethylene) adduct of ethylene diamine having a molecular weight from about 7,500 to about 27,000 wherein at least 40 weight percent of said adduct is poly(oxyethylene) has been found to be particularly advantageous for use in cleaning and conditioning both soft and hard contact lenses when used in amounts from about 0.01 to about 15 weight percent. The CTFA Cosmetic Ingredient Dictionary""s adopted name for this group of surfactants is poloxamine. Such surfactants are available from BASF Wyandotte Corp., Wyandotte, Mich., under the registered trademark xe2x80x9cTetronicxe2x80x9d. An analogous of series of surfactants, suitable for use in the present invention, is the poloxamer series which is a poly(oxyethylene) poly(oxypropylene) block polymers available under the trademark xe2x80x9cPluronicxe2x80x9d (commercially available form BASF).
Various other ionic as well as amphoteric and anionic surfactants suitable for in the invention can be readily ascertained, in view of the foregoing description, from McCutcheon""s Detergents and Emulsifiers, North American Edition, McCutcheon Division, MC Publishing Co., Glen Rock, N.J. 07452 and the CTFA International Cosmetic Ingredient Handbook, Published by The Cosmetic, Toiletry, and Fragrance Association, Washington, D.C.
Amphoteric surfactants suitable for use in a composition according to the present invention include materials of the type are offered commercially under the trade name xe2x80x9cMiranol.xe2x80x9d Another useful class of amphoteric surfactants is exemplified by cocoamidopropyl betaine, commercially available from various sources.
The foregoing surfactants will generally be present in a total amount from 0.01 to 5.0 percent weight by volume (w/v), preferably 0.1 to 5.0 percent, and most preferably 0.1 to 1.5 percent.
It may also be desirable to include water-soluble viscosity builders in the solutions of the present invention. Because of their demulcent effect, viscosity builders have a tendency to enhance the lens wearer""s comfort by means of a film on the lens surface cushioning impact against the eye. Included among the water-soluble viscosity builders are the cellulose polymers like hydroxyethyl or hydroxypropyl cellulose, carboxymethyl cellulose and the like. Such viscosity builders may be employed in amounts ranging from about 0.01 to about 4.0 weight percent or less. The present solutions may also include optional demulcents.
In a first embodiment of a method according to the present invention, the method comprises cleaning a contact lens with an aqueous solution comprising 0.005 to 1.0 percent by weight of at least one phosphonic acid compound, or its physiologically compatible salt, having 1 to 12, preferably 1 to 10 carbon atoms. The carbon atoms may be in the form of a substituted or unsubstituted branched or unbranched aliphatic, cyclic aliphatic, or aromatic groups or combinations thereof. Exemplary phosphonic acid compounds are those according to Formula (I) above. Preferably the phosphonic acid compound has 1 or 2 phosphonic acid groups which may be in salt form.
Preferably, the present method comprises soaking (no rubbing) a lens in the solution for a total period of time that is within a range of 2 hours to overnight, prior to direct placement of the lens in the eye. By the term xe2x80x9cdirect placementxe2x80x9d is herein meant that the solution is not diluted or rinsed off the lens with a different contact-lens solution prior to xe2x80x9cinsertionxe2x80x9d or placement on the eye.
In yet another embodiment of a method according to the present invention, the claimed solution may be used to clean a frequent replacement lens (FRL) that is planned for replacement after not more than about three months of use in the eye, or that is planned for replacement after not more than about 30 days of use in the eye, or that is planned for replacement after not more than about two weeks in the eye. Preferably, the lens is made from a polymer comprising about 0.0 to 5 mole percent repeat units derived from methacrylic acid (MAA), 10 to 99 mole percent of repeat units derived from hydroxyethyl methacrylate, and about 0.5 to 5 mole percent of cross-linking repeat units. Cross-linking repeat units may be derived, for example, from such monomers as ethyleneglycol dimethacrylate, divinylbenzene, and trimethylpropane trimethacrylate.
Separately from, or supplementally to, immersing a contact lens in a contact lens solution according to the present invention while the contact lens is outside the eye, the accumulation of proteins on hydrophilic contact lens can be further prevented by applying such a solution as eye drops. Thus, an opthalmologically safe solution comprising the claimed compound can be packaged in a container adapted for applying the solution as drops to the eye.
The hydroxypropyl methylcellulose (HPMC) functions to provide a desired level of viscosity and to provide demulcent activity. It is characterized as a mixed ether of cellulose containing a variable proportion of methoxyl and 2-hydroxypropoxyl groups and is purchased from Dow Chemical under the trademark Methocel E 15 LV -Premium. It is to be understood that the invention is not limited to any specific hydroxypropyl methylcellulose and that any equivalent HPMC of pharmaceutical grade may be used.
The ophthalmic solutions of this invention preferably contain a buffer system to control pH. Any pharmaceutically acceptable buffer system may be utilized. A preferred buffer system is provided by sodium borate/boric acid in amounts necessary to produce a pH of about 6.0 to 8.0. A preferred pH range is about 6.5-7.8 and a most preferred range is about 7.1-7.5.
The ophthalmic solutions of this invention are isotonic with respect to the fluids of the human eye. These solutions are characterized by osmolalities of 270-330 mOsm/kg. Osmolality of the solution of the invention is adjusted by means of sodium chloride and potassium chloride.
The solutions of the present invention may be formulated into specific contact lens care products, such as wetting solutions, soaking solutions, cleaning and conditioning solutions, as well as purpose type lens care solutions, etc. and mixtures thereof.
The solutions according to the present invention are physiologically compatible. Specifically, the solution must be xe2x80x9cophthalmically safexe2x80x9d for use with a contact lens, meaning that a contact lens treated with the solution is generally suitable and safe for direct placement on the eye without rinsing, that is, the solution is safe and comfortable for daily contact with the eye via a contact lens that has been wetted with the solution. An ophthalmically safe solution has a tonicity and pH that is compatible with the eye and comprises materials, and amounts thereof, that are non-cytotoxic according to ISO standards and U.S. FDA (Food and Drug Administration) regulations. The solution should be sterile in that the absence of microbial contaminants in the product prior to release must be statistically demonstrated to the degree necessary for such products.
The present invention can be used with all contact lenses such as conventional hard, soft, rigid and soft gas permeable, and silicone (including both hydrogel and non-hydrogel) lenses, but is preferably employed with soft lenses. Such lenses are commonly prepared from monomers such as hydroxyethyl methacrylate, hydroxyethylmethyl methacrylate, vinylpyrrolidone, glycerolmethacrylate, methacrylic acid or acid esters and the like. Such lenses absorb significant amounts of water, which amounts range from about 4 to about 80 percent by weight. Preferably, the invention is formulated as a xe2x80x9cmultipurpose solution,xe2x80x9d meaning that the solution may be used for cleaning, chemical disinfection, storing, and rinsing a contact lens. Such solutions may be part of a xe2x80x9cmultipurpose solution systemxe2x80x9d or xe2x80x9cmultipurpose solution package.xe2x80x9d The procedure for using a multi-purpose solution, system or package is referred to as a xe2x80x9cmulti-functional disinfection regimen.xe2x80x9d Multi-purpose solutions do not exclude the possibility that some wearers, for example, wearers particularly sensitive to chemical disinfectants or other chemical agents, may prefer to rinse or wet a contact lens with another solution, for example, a sterile saline solution prior to insertion of the lens. The term xe2x80x9cmultipurpose solutionxe2x80x9d also does not exclude the possibility of periodic cleaners not used on a daily basis or supplemental cleaners for removing proteins, for example enzyme cleaners, which are typically used on a weekly basis. By the term xe2x80x9ccleaningxe2x80x9d is meant that the solution contains one or more cleaning agents in sufficient concentrations to loosen and remove loosely held lens deposits and other contaminants on the surface of a contact lens, especially if used in conjunction with digital manipulation (for example, manual rubbing of the lens with a solution) or with an accessory device that agitates the solution in contact with the lens, for example, a mechanical cleaning aid. The critical micelle concentration of a surfactant-containing solution is one way to evaluate its cleaning effectiveness.
A multipurpose solution preferably has a viscosity of less than 75 cps, preferably 1 to 50 cps, and most preferably 1 to 25 cps and is preferably is at least 95 percent weight by volume water in the total composition.
As stated, the multipurpose solution of the invention is useful for cleaning contact lenses. Although the multipurpose solution effectively cleans and disinfects by simply soaking a lens in the subject solution, the multipurpose solution cleans more effectively if a few drops of the solution are initially placed on each side of the lens, and the lens is rubbed for a period of time, for example, approximately 20 seconds. The lens can then be subsequently immersed within several milliliters of the subject solution. Preferably, the lens is permitted to soak in the solution for at least four hours. Furthermore, the lens is preferably rinsed with fresh solution after the rubbing step and again after being immersed within the solution. If the subject solution includes an antimicrobial agent, the subject solution not only cleans the lens, but also disinfects. However, it will be appreciated that other xe2x80x9cnon-chemicalxe2x80x9d disinfection means may be used, e.g. heat disinfection.
Although not generally necessary, enzymatic cleaners may also be used with the multipurpose contact lens solutions of the invention, especially for patients susceptible to high levels of protein deposition. If used, enzymatic tablets may be placed directly within the subject solution, is a manner like that described in U.S. Pat. No. 5,096,607.

Composition and method for inhibiting uptake of biguanide antimicrobials by hydrogels


Compositions useful for treating inflammatory diseases including arthritis are disclosed which comprise cetyl myristoleate compounds or related compounds and at least one compound useful for treatment of inflammatory disease, such as tetracycline compounds, Cox-2 inhibitors, non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroids, local anaesthetics, chelating agents, matrix metalloprotease inhibitors, inhibitors of inflammatory cytokines, glucosamine, chondroitin sulfate and collagen hydrolysate. Also disclosed are pharmaceutical compositions and methods of treatment for inflammatory disease and local inflammation and dermal irritation. Also disclosed are compositions including tetracycline and at least one compound useful for treatment of inflammatory disease.

The present invention provides compositions and methods for prevention and treatment of arthritis and other inflammatory and autoimmune diseases.
The present invention relates to a method for treating inflammatory disease to prevent or delay the progression of the disease process or to alleviate the symptoms thereof. Diseases and disorders which have significant inflammatory components are ubiquitous. Skin disorders, bowel disorders, certain degenerative neurological disorders, arthritis, autoimmune diseases and other illnesses afflict many patients. In certain disorders, infectious agents may be directly or indirectly responsible for the entire disease process. In other disorders, an infectious or other agent may in some way facilitate an autoimmune or inflammatory response. For many patients, dietary or environmental factors may trigger an autoimmune or inflammatory response. In many patients genetic factors can play a key role. In the majority of cases, the causative elements have not been defined and many of the key pathophysiological components have not been elucidated. Accordingly, treatment options for the majority of these diseases is suboptimal.
Currently, steroids, nonsteroidal anti-inflammatory agents (NSAIDs), aspirin compounds and cancer chemotherapeutic immunosuppressive agents are often used. These agents often do not provide adequate symptomatic relief and are not believed to alter the natural progression of the disease. Indeed, some of these agents may make the disease worse. Furthermore, powerful side effects are found with most all of these therapies. Hence, there is a great need for safe and effective therapy for these disorders.
Cetyl myristoleate has been used for treatment of rheumatoid arthritis (Diehl, U.S. Pat. No. 4,113,881) and osteoarthritis (Diehl, U.S. Pat. No. 5,569,676), but there are many patients who do not achieve satisfactory results with this compound.
Tetracycline compounds have been found to weakly decrease collagenase and other enzyme activity and decrease certain kinds of cartilage damage found in canine models. However, human trials have been disappointing thus far. Side effects include dizziness gastrointestinal upset, nausea, and diarrhea.
The invention disclosed herein relates to the use of cetyl myristoleate (CMO) and CMO compounds in combination with other compounds useful for treating inflammatory disease. The invention is useful for protection against the development of arthritis and other inflammatory diseases and to provide relief of symptoms in individuals where such disease has been diagnosed. Cetyl myristoleate compounds have herein been found to be particularly useful when used in combination with components of accepted therapies. When used in this manner, cetyl myristoleate compounds can provide significant symptomatic relief.
Certain pharmaceutically active compounds or combinations thereof can be coadministered with CMO compounds, but can have significant adverse side effects. Coadministration with CMO compounds allows the use of reduced amounts of such treatment components and reduction or elimination of their undesired or detrimental side effects.
Certain therapies which provide relief from symptoms of inflammatory disease may not be effective for treating underlying causes of the disease. CMO compounds can be used to supplement those therapies to slow disease progression or to improve patient outcome.
The present invention further contemplates a composition comprising CMO compounds and a pharmaceutically acceptable vehicle as well as methods of treatment which comprise the use of those compositions.
The invention also relates to the use of tetracycline compounds in combination with other compounds useful for treating inflammatory diseases.
The invention discloses compositions and methods for topical treatment of inflammation resulting from envenomation or contact with other irritants. Such compositions comprise local anaesthetics, either alone, or in combination with one or more of proteases, steroids, tetracycline compounds, and CMO compounds. Such compositions may further comprise ingredients which enhance absorption.
Compositions of the invention comprise CMO and/or CMO compounds in combination with another substance known or thought to be useful for treatment of inflammatory disease. As used herein, CMO compounds refers to cetyl myristoleate and related compounds. These related compounds are esters of an unsaturated fatty acid and an alcohol. Unsaturated fatty acids include, for example, palmitoleic acid, oleic acid, linoleic acid, arachidonic acid, nervonic acid and the like. Preferred unsaturated fatty acids have cis double bonds. Furthermore, preferred unsaturated fatty acids have 12 or more carbon atoms. The preferred alcohol is long chain. Long chain alcohols have 10 or more carbon atoms and can be linear or branched. As used herein the term xe2x80x9cmodified cetyl myristoleate compoundsxe2x80x9d refers to the CMO compounds of the invention other than cetyl myristoleate itself, as described above.
According to one embodiment, compositions of the invention are pharmaceutical compositions which include one or more CMO compounds and at least one additional compound having potential utility for treatment of arthritis and other related inflammatory, autoimmune diseases or inflammatory diseases. Examples include, for example, tetracycline compounds, doxycycline, NSAIDs, and Cox-2 inhibitors, steroids (e.g. cortisone), cancer chemotherapeutic agents, chelating agents such as EDTA, inhibitors of tumor necrosis factor (TNF)(e.g. Embrel(copyright)), metalloprotease inhibitors, glucosamine, chondroitin sulfate, methyl sulfonal methane (MSM), S-adenosylmethionine (SAME) or other sulfur or methyl group donors, and synovial fluid supplements (e.g. Synvisc(copyright) and Hyalagan(copyright)).
Accordingly, one composition of the present invention includes a CMO compound and at least one compound selected from the group consisting of a tetracycline compound, a Cox-2 inhibitor, a non-steroidal anti-inflammatory drug (NSAID), a corticosteroid, a chelating agent, a matrix metalloprotease inhibitor, an inhibitor of inflammatory cytokines (e.g., interleukin inhibitor, inhibitor of interleukin synthetases), a local anaesthetic, glucosamine, chondroitin sulfate and collagen hydrolysate. As used herein, tetracycline compounds include, but are not limited to, tetracycline, doxycycline, minocycline, tetracycline homologs and modified tetracycline compounds.
A second composition of the invention includes a tetracycline compound and at least one compound selected from the group consisting of a Cox-2 inhibitor, a corticosteroid, a chelating agent, a matrix metalloprotease inhibitor, an inhibitor of inflammatory cytokines (e.g., interleukin inhibitor, inhibitor of interleukin synthetases), a local anaesthetic, glucosamine, chondroitin sulfate and collagen hydrolysates.
According to another embodiment of the invention are compositions for the treatment of inflammatory diseases, which includes a modified cetyl or sphingo myristoleate compound, with or without an additional compound.
Compositions of the invention can be used for treatment of arthritis. The present invention is also applicable to other autoinflammatory diseases as well as degenerative bone and joint diseases including osteoarthritis, crystal arthritis and capsulitis and other arthropathies. Further, the methods and compositions can be used for treating tendonitis, ligamentitis and traumatic joint injury.
The invention further contemplates treatment of other inflammatory immune disorders, including but not limited to rheumatic diseases, allergic disorders, asthma, allergic rhinitis, skin disorders, gastrointestinal disorders such as Crohn""s disease and ulcerative colitis, transplant rejection, poststreptococcal and autiommune renal failure, septic shock, systemic inflammatory response syndrome (SIRS), adult respiratory distress syndrome (ARDS) and envenomation.
The invention further contemplates utilizing CMO compounds alone or in combination with another compound for the treatment of inflammatory bowel disease. Poor gastrointestinal absorption following ingestion of a CMO compound leads to increased distal intraluminal delivery of these compounds to the distal gastrointestinal tract. Such action places the compound in direct topical proximity to diseased intestinal, colonic or rectal mucosa or other tissues.
In an embodiment of the present invention, the amount of a CMO compound to be administered per day is from about 25 mg to about 1000 mg. More preferably, the amount of the CMO compound is from about 75 mg to about 750 mg.
Tetracycline compounds affect protein synthesis and appear to have anti-inflammatory properties in addition to their anti-microbial properties which are useful for treatment of arthritis. For example, there are other antibiotics that may be useful, and perhaps even more effective at killing acne bacteria but tetracycline compounds are more effective in treating acne. It is believed by the inventor that this is a result of tetracycline""s anti-inflammatory activity. The anti-inflammatory activity of tetracycline compounds make them useful for treating other inflammatory disorders, even in the absence of an infectious agent. Tetracycline compounds can inhibit enzymes associated with inflammatory diseases such as matrix metalloproteases (MMPs), collagenase, gelatinase and elastase. While it is widely thought that tetracycline compounds decrease enzyme activity by chelation, they may also decrease inflammation by decreasing production of proinflammatory or other compounds. Tetracycline compounds may be effective when used with other compounds in the treatment of inflammatory conditions.
As used herein, tetracycline compounds include tetracycline and modified tetracyclines which may or may not have altered biological activity. For example, modification at specific positions can lead to the loss of antimicrobial bioactivity. See, e.g. Mitscher, The Chemistry of Tetracyclines, p.211 (1978). Examples of modified tetracycline compounds are those which lack the dimethylamino group at position 4 and tetracycline compounds modified at the 2-carbon position to produce a nitrile. According to the invention, a variety of tetracycline compounds can be employed, including those having reduced antimicrobial activities provided they retain anti-inflammatory activity. Examples of preferred tetracycline compounds include, but are not limited to doxycycline, minocycline, 4-dedimethylaminotetracycline, 6-fluoro-6-demethyltetracycline and other chemically modified tetracycline compounds.
In a preferred embodiment, a composition of the invention comprises at least one CMO compound and at least one tetracycline compound. The amount of tetracycline compound used according to the invention is an amount effect for treating an inflammatory disease and need not be a dose used for antimicrobial treatments. When the tetracycline compound is doxycycline, the dose for a human can be from about 5-10 mg to about 800 mg daily. Similarly, other tetracycline compounds can be used in normally prescribed amounts or in lesser doses which maintain effectiveness but reduce unwanted side effects. For example, the amount of tetracycline compounds used can be from about 10 mg to about 1200 mg.
When using CMO compounds and tetracycline compounds in combination, the particular dosage combination to be used for any individual is easily determinable. For example, when determining effective dosage for the relief of pain of arthritis, the practitioner will start with a recommended dose of the tetracycline compound and then adjust the amounts of the components to determine the smallest dosage which provides effective pain relief. For example, in a preferred embodiment, where the tetracycline compound is doxycycline, doxycycline can first be administered in a daily dose of up to about 800 mg, followed by a reduction to a minimal effective amount. The minimal effective dose can be about 5-10 mg or lower. A preferred dose is about 100 mg. When the combination is administered, for example, to suppress development of an inflammatory disease, the minimal effective amount to be administered can be determined by monitoring symptoms of the disease and determining the smallest dose which results in symptom suppression. Symptoms of the disease can be monitored by any invasive or noninvasive means which is convenient for measuring relevant aspects of the disease. For example, where the disease is osteoarthritis or another inflammatory joint disease, progression can be measured by determining amounts of collagenase in synovial fluid, by X-rays, or by other well known evaluation procedures which are applicable to the disease. Higher doses may be needed to inhibit the actual progression of the disease process pathophysiology.
In another embodiment, the composition comprises at least one CMO compound and a NSAID or Cox-2 inhibitor. The amount of CMO compound to be administered per day is from about 25 mg to about 2000 mg. More preferably, the amount of CMO compound is from about 75 mg to about 750 mg. The amount of the NSAID or Cox-2 inhibitor to be administered for treatment of an inflammatory disease is an amount effective in combination with CMO compound to provide relief from pain or other symptoms of the disease, or to provide a significant reduction in one or more indications of disease progression. The NSAID may be selected from the various classes of such compounds, and include for example, salicylates such as acetylsalicyclic acid, and diflunisal, acetic acids such as indomethacin, sulindac, tolmetin, diclofenac, and etodolac, propionic acids such as flurbiprofen, naproxen, ketoralac, and ketoprofen, fenamates such as meclofenamate, oxicams such as piroxicam, and oxindoles such as tenidap. Other NSAIDs and Cox-2 inhibitors contemplated by the invention include, but are not limited to ibuprofen, flosulide, diclofenac, meloxicam, Celecoxib (i.e. Celebrex(copyright) or SC-58635), and Rofecoxib (i.e. Vioxx(copyright), 4-(4xe2x80x2-methylsulfonylphenyl)-3-phenyl-2-(5H) furan-2-one, or MK-0966).
In a further exemplary embodiment, the composition comprises at least one CMO compound, a tetracycline compound and a Cox-2 inhibitor. The amount of CMO compound to be administered per day is from about 25 mg to about 1000 mg. More preferably, the amount of CMO compound is from about 75 mg to about 750 mg. Where doxycycline is used as the tetracycline compound, the amount to be administered can be from about 5-10 mg to about 800 mg daily. The Cox-2 inhibitor is in an amount which, when combined with CMO compound and tetracycline compound, results in a relief of symptoms or a significant reduction in one or more indications of disease progression.
According to the invention, CMO compounds can be used in combination with corticosteroids for treatment of inflammatory diseases. Corticosteroids are commonly used for treatment of certain inflammatory diseases and conditions. For example, periarticular injection of methylprednisolone (Depo-Medrol) can be effective for treatment of clinical sacroiliitis in patients with seronegative spondylarthropathy. Glucocorticoids are potent anti-inflammatory agents that play an important role in the therapy of many patients with connective tissue diseases, including systemic lupus erythematosus, polymyalgia rheumatica, various types of vasculitis, and complications of rheumatoid arthritis. Glucocorticoids reduce the function of lymphocytes, monocytes, and eosinophils in peripheral blood and inhibit release of lysosomal enzymes. Glucocorticoids have proved to be effective in the treatment of inflammatory manifestations of disease, but long term dosing of increasing amounts are often required with their attendant side effects becoming common and severe.
Among significant adverse effects of glucocorticoid therapy which can be minimized by the use addition of CMO compounds or tetracycline compounds and the reduction in the amount of glucocorticoids are osteoporosis, aseptic necrosis of bone, steroid myopathy, diabetes and defective collagen synthesis.
Other potentially useful compounds for inflammatory disease treatment which can benefit from the inclusion of CMO compounds or tetracycline compounds in the treatment regimen include chelating agents such as EDTA, metalloprotease inhibitors and various inhibitors of synthesis or activity of immunostimulatory factors such as tumor necrosis factor (TNF) and IL-1. Activated oxygen species and other mediating substances from triggered phagocytes appear to exacerbate and perpetuate the rheumatoid condition. Iron excesses are capable of aggravating arthritic inflammation, probably through their pro-oxidant potentials. Iron chelating drugs and anti-oxidants have potential for clinical use to reduce free radical-induced tissue damage in rheumatoid arthritis.
Matrix metalloproteases (MMPs) are a family of enzymes that can degrade all the components of the extracellular matrix. To prevent unlimited connective tissue destruction a number of inhibitors exist to limit their activity. Artificial inhibitors which are useful for preventing cartilage erosion include cartilage protective agent (CPA) Ro 32-3555 (Roche) and CGS 27023A (Ciba Geigy).
Treatment with a chimeric mAb to TNF-alpha has been shown to suppress inflammation and improve patient well-being in rheumatoid arthritis (RA). Examples of TNF antagonists shown to be effective for short term treatment include infliximab and etanercept. In addition, antagonism of the cytokine IL-1 may be useful for prevention of joint destruction.
Combination therapy using effective doses of CMO compounds or tetracycline compounds with chelating agents, MMP inhibitors or inhibitors of inflammatory compounds is contemplated.
CMO compounds or tetracycline compounds can be used in combination with one or more nutraceutical agents. Many nutraceuticals are believed to possess biological activities which are useful for disease treatment. Several studies claim glucosamine, chondroitin sulfate and collagen hydrolysate to be somewhat useful for symptomatic treatment of osteoarthritis. In an embodiment of the invention, treatment with CMO compounds and tetracycline compounds will slow cartilage and tissue deterioration and increase the effectiveness of these and other nutraceutical agents or factors which stimulate new cartilage formation, presumably by decreasing cartilage destruction.
Typically, the amount of glucosamine or chondroitin sulfate administered per day ranges from about 500 mg to about 2500 mg. CMO compounds can be administered in combination with the aforementioned agents to obtain increased benefit, for example, where stronger remedial effects are desired. The amount of CMO compound to be administered per day is from about 25 mg to about 1000 mg. More preferably, the amount of CMO compound is from about 75 mg to about 750 mg. Tetracycline compounds can be added for increased effectiveness.
Viscosupplementation of synovial fluid has been used for treatment of arthritis patients. For example, treatment of synovial fluid of RA patients with intra-articularly injected hyaluronate has been found to result in clinical improvement. In addition, synthetic crosslinked hyaluronans having improved viscosity characteristics, such as hylan G-F 20 (Synvisc), have been developed as therapeutic agents. Viscosupplementation has also been tested in combination with treatment with NSAIDs. According to the invention, CMO compounds or tetracycline compounds are used in combination with such treatments in a dose from about 25 mg to about 1000 mg. More preferably, the amount of CMO compounds is from about 75 mg to about 750 mg.
With regard to arthritis and inflammatory joint diseases, treatment is indicated when joint disease is suspected from, for example, clinical or radiographic findings. Clinical signs of joint disease include lameness, pain, joint capsule distension, periarticular soft tissue swelling, crepitus, laxity, and thickening or enlargement of a joint by fibrosis or osteophytosis. Radiographic indications for arthroscopy include increased joint fluid, joint capsule thickening, periarticular soft tissue swelling, osteophyte formation, sclerosis, joint space narrowing, cartilaginous or osseous deformities or defects, bone chips or fragments, and joint laxity or subluxation.
Conditions which can diagnosed arthroscopically include osteochondritis dissecans (OCD) of the shoulder, and elbow, meniscal injuries, partial and complete cruciate ligament ruptures, fragmentation of the medial coronoid process, degenerative joint disease, intra-articular fractures, synovitis, bicipital tendonitis, bicipital tendon rupture, and neoplasia.
Cartilage lesions can be detected before the onset of degenerative joint disease. Obtaining biopsy specimens of synovial membrane from more than one joint with a minimally invasive technique is particularly helpful in the diagnosis of immune-mediated arthropathies.
It is discovered herein that certain local anaesthetics can be used to reduce symptoms of envenomation, particularly inflammation, when topically applied. In general, localized inflammation and dermal irritation can be similarly treated. Causes of such inflammation or irritation include, but are not limited to, contact with toxins, immunogens or other irritants. Although teatment of human subjects is exemplified, treatment of other mammals is contemplated as well.
Local anaesthetics include for example lidocaine, ropivicaine, prilocaine, americaine, benzocaine, bupivicaine, long acting topical anaesthetic (LTA; AstraZeneca), EMLA(copyright) (eutectic mixture of local anaesthetics; AstraZeneca) anaesthetics (from Astra Pharmaceuticals), and other eutectic mixtures of local anaesthetics. EMLAI(copyright) is a mixture of lidocaine and prilocaine in a ratio of about 1:1. It is understood that for compounds with a chiral center, levo, dextro or an optimum mixture may provide therapeutic benefit. For example, the levo form of ropivicaine and bupivicaine provide a degree of vasoconstriction relative to the dextro forms of these compounds.
In an embodiment of the invention, the local anaesthetic is used in combination with CMO compounds, tetracycline compounds, papain or other proteases or peptidases, steroids or topical antibiotics to reduce inflammation, pain or infection risk. The CMO compounds, tetracycline compounds, papain or other proteases or peptidases, steroids, or topical antibiotics can be topically applied or administered by another route. For such treatments, the local anaesthetic will usually be topically applied. Local anaesthetics typically are applied in amounts as are known in the pharmaceutical art and commonly used to deaden sensation. For topical application steroids are used in concentrations typically available in commercially available creams and salves and in an amount sufficient to cover the area to be treated. Tetracycline compounds are applied in amounts from about 10 xcexcg to about 1000 xcexcg. CMO compounds are useful when applied in amounts from about 25 xcexcg to 500 xcexcg. Proteases are typically formulated in ointments or other vehicles in an amount from 1% to 50% by weight.
It will be apparent that topical preparations may further comprise substances which enhance absorption. Such absorption enhancers are well known to those of ordinary skill in the art. Examples include, but are not limited to dimethyl sulfoxide (DMSO), fatty acids, micelles, and microsome and liposome preparations. Furthermore, DMSO or related compounds can have analgesic or anti-inflammatory properties.
Compositions can be administered by a variety methods which are well known in the art. Routes of administration include, but are not limited to oral, topical, sublingual, rectal, intranasal, intraocular, intravenous, intramuscular, transdermal, and by inhalation.
However, for delivery to specific sites of inflammation, other means can be used for administering the composition such as, for example, by intraarticular, periarticular or intraosseous injection. Delivery methods can employ microsomes or liposomes. Where desirable, active components can be formulated into timed-release products. Target specific delivery may be helpful as in colonic delivery of tetracycline compounds, CMO compounds, local anaesthetics or other agents to patients with colitis, or using transport peptides to bring effective compounds deeper into joint collagen or other tissues.
In addition, active components can be delivered locally to specific sites of action, for example by intraarticular, periarticular and intraosseous injection. For treatment of envenomation by insects or other animals, topical application of a proteolytic enzyme (e.g., papain or stromolysin, collagenase) and local anaesthetics is effective in relieving pain and decreasing inflammation. The addition of CMO compounds or tetracycline compounds to the therapy, applied topically or otherwise administered, can further increase efficacy.
There is no requirement that active components used in treatment be administered by the same route or at the same time. For example, in one embodiment, a tetracycline compound is administered orally according to a first schedule and CMO compound is administered orally according to a second schedule. In another embodiment, a tetracycline compound and a Cox-2 inhibitor are injected and a CMO compound is administered orally. In a further embodiment, viscosupplementation by intraarticular injection is combined with intraarticular administration of a CMO compound.
For the purposes of the invention, xe2x80x9cpharmaceutically acceptable vehiclexe2x80x9d means any of the standard pharmaceutical vehicles. Vehicles include any and all solvents, dispersion media, coatings, bandages, patches, antibacterial and antifungal agents, isotonic and absorption delaying or enhancing agents, transport polypeptides and lipids, sweeteners and the like. The pharmaceutically acceptable vehicles may be prepared from a wide range of materials including, but not limited to, diluents, binders and adhesives, lubricants, disintegrants, coloring agents, bulking agents, flavoring agents, sweetening agents and miscellaneous materials such as buffers and absorbents that may be needed in order to prepare a particular therapeutic composition. The use of such media and agents with pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions.
Examples of suitable vehicles are well known in the art and include, but are not limited to, any of the standard vehicles such as phosphate buffered saline, phosphate buffered saline containing Polysorb, water, emulsions such as oil/water emulsion, and various types of wetting agents. In a preferred embodiment, pharmaceutical compositions of the invention are for administration to a human. Alternatively, a pharmaceutical composition can be administered to any animal.
In the case of treatment of joint diseases, it is helpful to reduce forces exerted on affected tissues. For example, treatment of joint diseases according to the invention can include reduction of gravitational or other forces acting on the affected joint or at vulnerable locations of the affected joint. External tractions or mechanical support devices (e.g., specially shaped foam or other viscoelastic compositions) which decrease forces acting on the affected joint will be helpful. Splinting of the hand to maintain a joint in a neutral position can help treatment of joints of the hand. Similarly, other joints can be appropriately supported.
For reduction of inflammation and associated discomfort, increasing ambient pressure, for example, by using hyperbaric devices, submersion, or other means, can also be used to increase the effects of the treatments described herein.
Throughout this application, various publications, patents, and patent applications have been referred to. The teachings and disclosures of any publications, patents, and patent applications referred to hereins are hereby incorporated by reference, in their entireties, into this application to more fully describe the state of the art to which the present invention pertains.
It is to be understood and expected that variations in the principles of invention herein disclosed may be made by one skilled in the art and it is intended that such modifications are to be included within the scope of the present invention.

Methods and compositions for treatment of inflammatory disease


A stent shaped as a three-dimensional body which is formed by interlaced threads (1) arranged in multistart turns of a helical line. The threads (1) are arranged in at least two groups (2 and 3) of the helical turns featuring opposite senses of helix. The stent ends are established by sections (5) where the turns of one helical line merge into those of the other helical line, said sections appearing as a single length of the thread (1).

The present invention relates in general to medicine and more specifically to surgery and can find predominant application for endoreconstruction of blood vessels and other hollow organs and structures of human body. The invention also enables one to carry out reconstruction of perforating lesions.
Modern medicine is capable of reconstructing blood vessels, ducts, and perforating lesions of human organs, using special framework-type devices named stents. Use of stents makes it possible to restore the natural function of an defected anatomical structure without having recourse to direct operative interference techniques.
In order to function as an effective and reliable endoprosthesis stents must possess a number of specific properties. First and foremost stents must provide unobstructed motion of body fluids through the implanted structure. Such stents must be very flexible and at the same time must be rigid enough to withstand the pressure exerted by walls of blood vessels or body cavities, with uniform pressure distribution over entire side surface of the stent. Moreover, the stent construction must be convenient for being transported to the zone of reconstruction and positioned there, as well as must not produce any or at least a minimal injurious effect upon the surrounding tissues in the course of implantation and further functioning.
One state-of-the-art hollow tubular stent is known to have end portions and a surface formed by a plurality of intersecting elastic elements at least part of which are interconnected at the stent ends (U.S. Pat. No. 733,665).
The stent can be of two different diametrical dimensions due to radial deformation of its elastic elements. Before being positioned at the place of reconstruction the stent is deformed so as to minimize its diametrical dimension. Then the stent is placed, in the deformed state, inside a transporting means by arranging it on a special setting bulb or balloon. Once the stent has been transported to the place of reconstruction the setting bulb or balloon is expanded so that the stent diameter is maximised.
It is due to its rigid construction that the stent withstands rather high pressure of the walls of the organ being prosthesized and provides for a uniform distribution of the resultant stresses over the prosthesized surface.
However, the stent in question features but lower elasticity due to a restricted axial deformation, which affects the quality of endoprosthesizing.
Another prior-art stent is known to be in the form of a hollow tubular springlike body made of a material having a shape memory effect (SME). Stents made from such a material are capable of restoring their shape upon a change in the temperature conditions.
The advantages of said stent are determined by the properties of the material it is made from that provides for complete restoration of the stent shape in the zone of reconstruction, as well as a possibility of its convenient withdrawal from the organ being prosthesized upon cooling of the stent. The procedure of the stent positioning is improved, too.
A variety of stent embodiments are possible. In particular, the stent may have a construction disclosed in the aforediscussed invention (U.S. Pat. No. 733,665).
One more stent embodiment presents its construction as a hollow tubular element established by the coils of a wire or the turns of a strip. The construction of such a stent is more elastic since the stent is deformable both radially and axially.
However, with this stent it is not always possible to provide and optimum value of the pitch of spring coils or of strip turns because with too a large pitch a uniform pressure distribution over the surface being prosthesized is affected, which may result in partial vessel stenosis, whereas in the case of too a small pitch stent implantation may cause hyperplasia of the intima of the vascular wall in the organ under reconstruction, as well as early thrombotic complications.
Still more stent of the prior art is known to appear as a three-dimensional tubular structure established by a number of interlaced rigid and/or elastic threads arranged in two groups along helical lines directed oppositely to each other. Ends of these helical threads are not connected to one another or to helical portions of other threads but are arranged loosely at both ends of the tubular structure.
The stent under consideration is elastic and easily deformable, and can be placed in a small-diameter delivery systems; besides, the stent provides for an adequate rigidity and a uniform pressure distribution over the surface being proshesized.
However, the presence of free ends of threads on the stent end faces can adversely affect the framework properties as a whole. To attain the required rigidity involves increasing the number of threads used, which is undesirable since this may cause intimal hyperplasia and early thrombotic complications. The ends of threads loosely arranged at the ends of the tubular structure can produce an injurious effect upon walls of a blood vessel; in addition, more complex devices are required to deliver the stent to a required location inside a body.
Known in the present state of the art is a stent in the form of a three-dimensional structure formed by interlaced threads arranged in multistart turns of a helical line (RU, A, 1,812,980). The turns form at least two groups featuring opposite senses of the helical line. The thread is made of a meterial featuring the SME. The ends of threads belonging to different groups are fixedly joined together on the end faces of the three-dimensional structure by, e.g., spot welding or splicing together.
The stent under discussion provides for a required rigidity and a uniform pressure distribution over the surface being prosthesized, as well as possesses elasticity.
It is due to joined together ends of threads on the stent end faces that its placing into a transporting system is simplified. The selected stent material ensures virtually complete restitution of its shape at the place of the prosthesis implantation.
However, an artificial joining of threads results in a local change of the physic-mechanical properties of the stent, which tells negatively on the rigidity and reliability of the stent construction as a whole. Moreover, the presence of artificial joints between the threads on the stent end faces gives one no way of attaining a maximum possible stent transformation which in turn places limitation on a possibility of its placing into a small-diameter delivery systems.
The present invention has for its principal object to provide a stent with a broad range of functional applications, possessing the required rigidity and elasticity, as well as a high degree of the shape transformation.
The foregoing object is accomplished due to the fact that in a stent shaped as a three-dimensional body which is formed by interlaced elastic threads arranged in multistart turns of a helical line and in at least two groups featuring opposite senses of the helix line, according to the invention, the ends of the three-dimensional body are established by the sections where the turns of one helical line merge into those of the other helical line, said sections appearing as a bend of a single thread segment.
Thus, instead of joining the threads at both ends of the stent by welding, soldering or other similar means, these ends are connected by curvilinear segments made of the same piece of thread. Hence similar physic-mechanical properties are retained in the entire stent volume, while the sections of the thread merging at the stent ends acquire the properties of a spring and become the functionally active construction elements. The stent ends formed by all the aforesaid sections of the thread bend are capable of withstanding the pressure of the walls of the anatomy under reconstruction, and the stent construction acquires the required rigidity so that the stent provides for a uniform pressure over the surface being prosthesized. In addition, it is due to their elastic properties that the section of the thread bend tend to restore their original shape after their having undergone deformation, thereby taking an active part in the process of the stent shape restoration.
The herein-proposed stent construction features the required elasticity due to a possibility of its radial and axial deformation under the action of small forces applied thereto.
The stent construction provides for high degree of the transformation of the stent shape. In the case of longitudinal stent deformation the threads slide with respect to one another, with the result that the angle of their mutual arrangement changes, the stent diameter decreases and becomes equal in length. Hence the stent diameter is much reduced, whereas its length changes but rather inconsiderably. High degree of the transformation cenables one to place different-dimension stents into a minimised-diameter delivery systems, a future that solves the problem of transporting stent to the place of reconstruction along both major and minor blood vessels.
To attain the maximum degree of the stent transformation with the required construction rigidity remaining unaffected, it is expedient that the turns of all the helical lines are made of a single thread segment. Such a stent possesses high elasticity and transformation ability due to a low interlacing density and a small number of threads. In addition, low interlacing density tells positively on the quality of endoreconstruction because it reduces reaction of the walls being prosthesized to a foreign body being implanted.
It is expedient in some cases that the stent features variable-pitch turns so as to provide different interlacing density as for the stent length with a view to, eg.g., high-rate formation of the neointima of the vessel walls on individual reconstruction areas.
It is practicable that the stent is shaped as three-dimensional body having variable cross-section diameter as for the length thereof, a future that makes it possible to obtain a stent shape adapted for endoreconstruction of defects of the various types and configurations.
Whenever it becomes necessary to obtain higher-density thread interlacing on a preset area, it is expedient that the stent is provided with additionally interwoven threads on said area. Such a stent is applicable for, e.g., reconstructing an aneurysms vessel.
It is expedient that the free thread ends are joined on the surface of the three-dimensional body, to the threads that form helical turns, and/or to one another, thus adding to the stent reliability.
It is expedient that on the sections of merging, the turns of one helical line merge into those of the helical line with the opposite sense of the helix. In this case, the radius of curvature of the merging section is increased, and such sections become more resilient.
A bend or curvilinear segment connecting two helical elements made from the same thread can have various shapes, e.g. a circular arc, a loop, or an U-shape. Those merging sections are most elastic which are shaped as circle arcs having a large radius of curvature.
In some instances it is expedient that the points of bending the threads on the merging sections are arranged in different transverse planes relative to the longitudinal body axis. This makes it possible to attain more compact arrangement of the stent ends during its transformation.
It is expedient that the stent is made of a material possessing a SME or of a superelastic material. Such stent possess a virtually complete degree of shape restitution.
It is expedient that, with a view to reducing its thrombogenicity, in some instances the stent may be provided with a biocompatible material.
No sources of information have been found by the Applicants that would contain any data on tecnical solutions idetical or equivalent to the device proposed herein. This, in the Applicants"" opinion, renders the invention conforming to the condition of novelty (N).
Practical realisation of the specific features of the present invention imparts an important technical effect to the stent, consisting in that its required construction rigidity is attained along with high elasticity and transformation ability. The aforesaid novel feature of the present invention define, in the Applicants"" opinion, conformity of the herein-proposed technical solution to the inventive step criterion (IS).
Practical use of the herein-proposed technical solution provides for a number of positive properties that follow:
Required construction rigidity and uniform pressure distribution over the surface being prosthesized;
High stent elasticity;
High degree of the shape transformation, which enables the stent to be placed into a minimum-diameter delivery systems;
Lower traumatogenicity of the stent implanting procedure;
Broad range of functional applications.